Effect of hypoxia-inducible factor-1α induction by CoCl 2 on breast cancer cells survival: influence of cytochrome-c and survivin

  • Reni Paramita Doctoral student in Biomedical Study, Faculty of Medicine, Universitas Indonesia, Jakarta
  • Mohamad Sadikin Department of Biochemistry and Molecular Biology, Faculty of Medicine, Universitas Indonesia, Jakarta
  • Noorwati Sutandyo Department of Internal Medicine, Faculty of Medicine, Universitas Indonesia, Jakarta
  • Septelia I. Wanandi Department of Biochemistry and Molecular Biology, Faculty of Medicine, Universitas Indonesia, Jakarta
Keywords: apoptosis, cell viability, cytochrome-c, hypoxia-inducible factor-1α, survivin


Background: Tumor tissue usually became hypoxic due to disruption of oxygen supply. Adaptation response to hypoxia is mediated by transcription factor, hypoxia- inducible factor-1α (HIF-1α). HIF-1α signaling is known to increase the expression of pro-apoptotic protein cytochrome-c, and anti- apoptotic survivin. In this study we wanted to analyze the role of HIF-1α on breast cancer cells survival through pro-apoptosis cytohrome-c and anti-apoptosis survivin regulation.

Methods: Breast cancer cell lines T47D were induced by CoCl 2 then harvested to analyze the expression of HIF-1α, protein cytochrome-c, mRNA survivin and cell viabilities

Results: HIF-1α induction by CoCl2 causes the increase of protein and mRNA of HIF-1α, cytochrome-c protein, and survivin mRNA, but does not cause the changes in cell viability.

Conclusion: HIF-1α induction have no effects on breast cancer cell line T47D viabilities due to the balance regulation between pro-apoptosis expression cytochrome-c and anti-apoptosis survivin.


International Agency for Research on Cancer (IARC) [Internet]. Breast Cancer: Estimated Incidence, Mortality and Prevalence Worldwide in 2012. World Health Organization 2012. Available from: http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx

Okazaki T, Ebihara S, Asada M, Yamanda S, Niu K, Arai H. Erythropoietin promotes the growth of tumors lacking its receptor and decreases survival tumor-bearing mice by enhancing angiogenesis. Neoplasia. 2008;10(9):932-9.

Hill R, Bristow RG. The scientific basis of radiotherapy. In: Tannock IF, Hill RP, Bristow RG, Harrington L, editors. The basic science of oncology. 4th ed. Boston: Mc Graw Hill; 2005. p. 298.

Patel SA, Simon MC. Biology of hypoxia-inducible factor-2α in development and disease. Cell Death Differ. 2008;15(4):628-34. http://dx.doi.org/10.1038/cdd.2008.17

Fandrey J, Gorr TA, Gassmann M. Regulating cellular oxygen sensing by hydroxylation. Cardiovasc Res. 2006;71(4):642-51. http://dx.doi.org/10.1016/j.cardiores.2006.05.005

Mole DR. Iron homesotasis and its interaction with prolyl hydroxylases. Antioxid Redox Signal. 2010;12(4):445-58. http://dx.doi.org/10.1089/ars.2009.2790

Ke Q, Costa M. Hypoxia-inducible factor-1 (HIF-1). Mol Pharmacol. 2006;70(5):1469-80. http://dx.doi.org/10.1124/mol.106.027029

Ardyanto TD, Osaki M, Nagahama Y, Yamaga K, Maeta N, Tamura T, et al. Down-regulation of cobalt-induced HIF-1α expression correlates with cell proliferation and apoptosis in human gastric carcinoma cells. Oncol Report. 2008;19(2):339-43.

Greijer AE, van der Wal E. The role of hypoxia inducible factor 1 (HIF-1) in hypoxia induced apoptosis. J Clin Pathol. 2004;57(10):1009-14. http://dx.doi.org/10.1136/jcp.2003.015032

Mita AC, Mita MM, Nawrocki ST, Giles FJ. Survivin: key regulator of mitosis and apoptosis and novel target for cancer therapeutics. Clin Cancer Res. 2008;14(16):5000-5. http://dx.doi.org/10.1158/1078-0432.CCR-08-0746

Peng X, Karna P, Cao Z, Jiang B, Zhou M, Yang L. Cross-talk between epidermal growth factor receptor and HIF-1 signal pathways increases resistance to apoptosis by upregulating survivin gene expression. J Biol Chem. 2006;281(36):25903-14. http://dx.doi.org/10.1074/jbc.M603414200

Li F and Ling X. Survivin study: an update of 'what is the next wave'? J Cell Physiol. 2006;208(3):476-86. http://dx.doi.org/10.1002/jcp.20634

Maxwell P, Salnikow K. HIF-1: An oxygen and metal responsive transcription factor. Cancer Biol Ther. 2004;3(1):29-35. http://dx.doi.org/10.4161/cbt.3.1.547

Aulia G. Modulasi stress oksidatif pada ketahanan hidup sel punca kanker payudara (CD24-/CD44+) melalui induksi rotenone: tinjauan pada ekspresi manganese superoxide dismutase [tesis]. Jakarta: Universitas Indonesia; 2012. Indonesian.

Hendrawan S, Jusman SWA, Ferdinal F, Prijanti AR, Wanandi SI, Sadikin M. Expression of hypoxia inducible factor-1α (HIF-1α) gene and apoptosis in the heart induced by systemic hypoxia. Med J Indones. 2009;18(2):97-101. http://dx.doi.org/10.13181/mji.v18i2.344

Ardyanto TD, Osaki M, Tokuyasu N, Nagahama Y, Ito H. CoCl2-induced HIF-1α expression correlates with proliferation and apoptosis in MKN-1 cells: A possible role for the PI3K/Akt pathway. Int J Oncol. 2006;29(3):549-55.

Kothari S, Cizeau J, McMillan-Ward E, Israels SJ, Bailes M, Ens K, et al. BNIP3 plays a role in hypoxic cell death in human epithelial cells that is inhibited by growth factors EGF and IGF. Oncogene 2003;22(30):4734-44. http://dx.doi.org/10.1038/sj.onc.1206666

Galanis A, Pappa A, Giannakakis A, Lanitis E, Dangaj D, Sandaltzopoulos R. Reactive oxygen species and HIF-1 signalling in cancer. Cancer Lett. 2008;266(1):12-20. http://dx.doi.org/10.1016/j.canlet.2008.02.028

Tanaka K, Iwamoto S, Gon G, Nohara T, Iwamoto M, Tanigawa N. Expression of survivin and its relationship to loss of apoptosis in breast carcinomas. Clin Cancer Res. 2000;6(1):127-34.

Wu XY, Fu ZX, Wang XH. Effect of hypoxia-inducible factor 1-α on Survivin in colorectal cancer. Mol Med Rep. 2010;3(3):409-15.

Kanwar JR, Shen WP, Kanwar RK, Berg RW, Krissansen GW. Effects of survivin antagonists on growth of established tumors and B7-1 immunogene therapy. J Natl Cancer Inst. 2001;93(20):1541-52. http://dx.doi.org/10.1093/jnci/93.20.1541

Brizel DM. Chemical modifiers of radiation response. In: Perez CA, Brady LW, editors. Principles and practice of radiation oncology. 5th ed. Philadelphia: Lippincott-Raven Publisher; 2008. p. 611-19.

Sekarutami SM. Pengaruh hipksia terhadap angiogenesis dan proliferasi sel kanker serviks uteri: hubungannya dengan respon tumor terhadap kombinasi radiasi dengan karbogen-nikotinamdi (KON) sebagai hypoxia modifier [disertasi]. Jakarta: Universitas Indonesia; 2010. Indonesian.

How to Cite
Paramita R, Sadikin M, Sutandyo N, Wanandi SI. Effect of hypoxia-inducible factor-1α induction by CoCl 2 on breast cancer cells survival: influence of cytochrome-c and survivin. Med J Indones [Internet]. 2014Oct.15 [cited 2024Mar.1];23(3):139-42. Available from: http://mji.ui.ac.id/journal/index.php/mji/article/view/933
Basic Medical Research